Dr. Susan Slovin: My career goes back probably 40 years when immunotherapy meant that you tried to devise a variety of different platforms to influence the human immune response so that it recognizes and fights cancer. We didn’t have the same level of sophistication in understanding the inner mechanisms of the immune system we do now, and frankly, in the 1970s, we were just identifying that there were two cells that governed the immune system, B- and T-cells. The world, unfortunately, has become checkpoint-centric much to my dismay. I believe that people think that checkpoint inhibitors are synonymous with immunotherapy. There are other immune treatments that continue to be investigated, but may not be easily exportable into clinical practice due to their uniqueness and complexity in development. This is, in fact, the case with CAR T-cell therapy. CAR T-cells (chimeric antigen receptor T-cells) are another platform whereby we engineer a patient’s immune T-lymphocytes (a white blood cell that is known to fight the cancer cell) to treat their cancer. We’ve been focusing on patients with metastatic prostate cancer to the lymph nodes and/or bone tissue who have failed other therapies but have not had chemotherapy before. They essentially have had multiple hormonal therapies.

We are using the body’s immune system in a different way than checkpoint inhibitors.

The body has two cell types: first, we have B-cells, which produce antibodies. Antibodies are proteins in the blood that fight infection or recognize molecules that don’t belong there. And second, there are T-cells, which are white cells involved in immune surveillance and tumor cell killing. In other words, they scavenge the body looking for molecules that don’t belong. Molecules that don’t belong include foreign cells, bacteria, and viruses. And, remember that cells also go to the bathroom and they leave behind waste products that may be foreign to the immune surveillance cells. These cell products, along with cells that die as a result of radiation or chemotherapy, provide novel antigens or molecules that may never have been seen before by the immune system and may invoke the immune system to respond and protect the body.

The immune system does not react against things that don’t pose threats to it. But the use of CAR cells takes advantage of the fact that T-cells are the largest cell population in the body and that they are the ones involved in effecting an anti-cancer response.

T-cells are part of the CAR therapy approach called adoptive cell transfer. It’s a little different from what’s been done with Provenge (sipuleucel-T), which is, ironically, the first autologous (self-derived) immune cell product used for the treatment of a solid tumor for prostate cancer. What’s ironic about that is that here we are in the world of prostate cancer for which we have an approved immune-based therapy but which appears to be minimally responsive to the more widely and successfully used checkpoint inhibitors.

Unlike Provenge (sipuleucel-T), which stimulates the patient’s dendritic (antigen-presenting) cells, adoptive cell transfer uses only a particular population of the patient’s immune cells to treat their cancer, mainly their T-cells.

CARs are approved in two indications: acute lymphocytic leukemia and lymphoma, but as yet have not been demonstrated to have antitumor efficacy in solid tumors. They are formed by engineering T-cell receptors, which graft a molecule with particular specificity onto an immune effector cell (T-cell). Typically, these receptors are used to graft the specificity of a monoclonal antibody onto a T-cell (for example prostate-specific membrane antigen [PSMA]) with transfer of their coding sequence facilitated by retroviral vectors. The receptors are called chimeric because they are composed of parts from different sources. The upshot is to be able to develop an “armored CAR,” that allows the T-cell to seek out cells that express that same molecule and therefore will ultimately engage the cancer cell that expresses the molecule and kills it via a variety of mechanisms. These include the recruitment of other cell populations and soluble serum factors such as cytokines. In toto, these cell populations also signal to one another to seek and destroy what may be considered foreign to the body. While there are limitations to the technology, we take the T-cell and change or engineer its receptor to express other molecules that recognize a wide range of proteins on the cancer cell. As such, when the T-cell receptor notices that protein, it will immediately follow the cancer cell and bring with it the remaining part of the T-cell to try to affect the cancer.

You can put anything on the surface of that T-cell, any particular kind of molecule, and use it to identify the cancer cells that harbor that molecule.

In prostate cancer, we have PSMA, a molecule that is overexpressed on the surface of prostate cancer cells as they become more resistant to therapy. Our group has used PSMA as a focal point for CAR therapy. We’ve been learning a lot about how to use these cells. It’s a very costly enterprise, and it has not proven perfect yet in the world of prostate cancer. We were able to complete a 12-patient trial looking at CAR T-cells’ ability to track to cancer cells with PSMA on their surface. We know that these CAR cells can migrate to the cancer cells and persist at the site of disease, but they can be unstable and not proliferate sufficiently to continue to interact with the cancer.